Glutaminase and Mechanistic Target of Rapamycin (mTOR) Pathway (GLS/mTOR)

The combined glutaminase (GLS) and mechanistic target of rapamycin (mTOR) pathway represents a critical intersection between cellular metabolism and growth signaling. Glutaminase is the primary enzyme responsible for converting glutamine to glutamate, a process essential for the tricarboxylic acid (TCA) cycle and biosynthetic precursors in rapidly proliferating cancer cells (Source: UniProt O94925). mTOR is a serine/threonine kinase that integrates nutrient availability and growth factor signals to regulate protein synthesis and cell cycle progression (Source: UniProt P42345). In many cancers, mTOR signaling upregulates glutamine metabolism, and conversely, glutamine availability can activate mTORC1 (Source: PubMed 28467918). Simultaneous inhibition of these two nodes is a therapeutic strategy designed to disrupt compensatory metabolic pathways and enhance anti-tumor efficacy, particularly in tumors that exhibit glutamine addiction or resistance to single-agent mTOR inhibitors (Source: ClinicalTrials.gov NCT03428217). Clinical trials, such as the CANTATA study, have explored combining the GLS inhibitor telaglenastat with the mTOR inhibitor everolimus in renal cell carcinoma. By targeting both the energy supply and the growth signaling machinery, this combination aims to achieve synergistic tumor suppression.

Other names

GLS/mTOR axisGlutaminase-mTOR signalingGLS and mTORC1 pathwayGlutaminolysis-mTOR signaling axis

Dual inhibition of glutaminolysis and the PI3K/AKT/mTOR signaling axis to suppress tumor growth and overcome metabolic compensation.